Human cytomegalovirus (HCMV) causes one of the most common opportunistic infections in immunocompromised individuals, including organ transplant recipients and AIDS patients. Moreover, HCMV infections are also among the most common causes of oral diseases associated with AIDS patients, including oral lesions in gingival and buccal mucosa and xerostomia associated with impaired salivary gland function. Salivary glands are a major source of persistent virus and have also been shown to be a site for CMV latent infections. Viruses in saliva that are shed from the infected salivary glands are believed to be one of the major sources for oral infections as well as for horizontal transmission. Eliminating viral replication and infection in salivary gland is central to the control of HCMV oral transmission as well as systemic diseases associated with AIDS patients. Understanding the mechanism of CMV infections in salivary gland will provide insight into treatment and prevention of CMV-associated diseases. Using murine CMV (MCMV) infection of mice as a model system, the proposed study is to identify viral genes required for CMV replication in salivary gland and to study the functions of these viral determinants in supporting CMV infections in oral cavity. We have used a Tn-3 based transposon to develop a novel approach to construct MCMV mutants and have recently isolated two novel mutants that are attenuated in growth in salivary gland. In the proposed research, mice will be infected with viral mutants and those mutants that are defective in replicating in salivary glands will be isolated. The pathogenecity of these mutants will be studied, and the genes that are mutated will be identified. Moreover, the mechanism of how the identified viral determinants function in supporting MCMV infections in salivary gland will be investigated. These studies will identify viral determinants for infection in salivary gland and elucidate the functions of these genes in the development of CMV-associated oral diseases. Understanding the mechanism of CMV infection in salivary gland will facilitate the development of novel strategies for treatment and prevention of CMV-associated oral diseases as well as viral systemic infections.